A Single H2S-Releasing Nanozyme for Comprehensive Diabetic Wound Healing through Multistep Intervention

Diabetic wound healing presents a significant medical challenge and requires multistep interventions due to comprehensive wound environments, such as hyperglycemia, bacterial infection, and impaired angiogenesis. However, current multistep interventions are complicated and need on-demand sequential release and synergy of multicomponents. Herein, a H2S-releasing cascade nanozyme (FeS@Au), which is composed of ultrasmall gold nanocluster (AuNC) loaded on ferrous sulfide nanoparticle (FeSNP), is developed as a single component to regulate glucose level, eliminate infection, and promote angiogenesis, achieving multistep interventions for comprehensive diabetic wound treatment. The glucose oxidase-like activity of AuNC catalyzes glucose into gluconic acid and H2O2, which not only lowers the local glucose level but also decreases the local pH and increases H2O2 level to boost the peroxidase-like activity of FeSNP to generate abundant hydroxyl radical (reactive oxygen species, ROS), inducing ferroptosis-like death in drug-resistant bacteria. Additionally, FeSNP release H2S in the acidified environment to upregulate hypoxia-inducible factor-1 to enhance vascularization through upregulating the expression of vascular endothelial growth factor (VEGF) and other angiogenesis-related genes, reducing the damage to endothelial cells caused by excessive ROS produced by the nanozyme. In a full-thickness MRSA-infected diabetic rat model, FeS@Au significantly eliminates bacteria, enhances angiogenesis, promotes collagen deposition, and accelerates wound healing. This work presents a single nanozyme with H2S-release for multistep interventions, providing a versatile strategy for healing extensive tissue damage caused by diabetes.